Candidate: Dr. Nicholas Abend is an Associate Professor of Neurology and Pediatrics at the University of Pennsylvania and The Children's Hospital of Philadelphia. His career goal is to be an expert clinical trialist leading development of interventions that improve outcomes among children with acute brain injuries. He is completing the fifth year of a K23 Mentored Career Development award from NINDS addressing the epidemiology of electrographic seizures (ES) in critically ill children and the impact of ES on neurobehavioral outcomes. Since 2007, he has published 52 peer-reviewed research papers, including 45 related to critical care EEG and seizure management with 33 as first or senior author. To advance this line of investigation, Dr. Abend needs to extend his observational studies into interventional clinical trials capable of establishing whether optimized ES interventions improve neurobehavioral outcomes. The proposed training in clinical trial design, execution, data management, and team-science skills will optimally position Dr. Abend to conduct multi-center clinical trials of innovative neuroprotective strategies for children with acute brain injuries. Research: Dr. Abend?s K23 research has demonstrated that ES occur in 10-40% of children with acute brain injuries, and that EEG monitoring is required for identification since most ES lack any observable clinical correlate. Additionally, he has shown that high ES exposure is associated with unfavorable neurobehavioral outcomes after adjusting for brain injury severity and critical illness severity. Based on these data, an increasing number of children are undergoing EEG monitoring in pediatric intensive care units, and recent guidelines recommend widespread EEG monitoring use in critically ill children with acute brain injuries to identify ES. However, it is concerning that children experiencing high ES exposures have unfavorable outcomes despite current clinical efforts to manage ES. This problem prompts a critical need to develop optimized ES management strategies that are more targeted, appropriate, and timely to better mitigate ES induced secondary brain injury. Dr. Abend?s overall objective is to address several clinical trial readiness gaps important in conducting subsequent clinical trials of optimized ES management. Aim 1 will generate and validate a predictive model using clinical and EEG variables to discriminate between acutely encephalopathic critically ill children who will and will not subsequently experience high ES exposures. This cohort is known to have worse outcomes with current management and would be predicted to benefit from optimized management. Determining the cohort?s characteristics will be the foundation for selecting a cohort for subsequent clinical trials of ES management. Aim 2 will determine the safety and feasibility of a targeted and timely ES management intervention in critically ill children. In contrast to standard care which slowly identifies ES and escalates medications, the high-intensity multi-modal intervention consists of frequent full-array EEG review, rapid anti-seizure medication initiation following ES onset, and rapid administration of sequential anti- seizure medications at high doses if ES persist. In working towards a clinical trial addressing ES management, sub-aims will assess other clinical trial readiness gaps including the number of eligible patients, participant and clinician randomization willingness, and statistical analysis of outcome measure variation which will provide effect size estimates to inform the design of subsequent trials. Aim 3 will provide Dr. Abend with advanced training in multi-center clinical design and execution using a combination of advanced didactic coursework, training from investigators experienced in leading acute neurologic clinical trials, and practical experience conducting a clinical trial (Aim 2). This research is innovative since it will develop the first model to predict high ES exposure and thereby identify an optimal cohort for inclusion in subsequent studies, and it will perform the first safety and feasibility assessment of a standardized ES intervention in critically ill children. These contributions are significant because they provide a foundation for subsequent clinical trials that will potentially yield new neuroprotective strategies for children with acute brain injuries. Environment and Career Development: The training plan builds upon the mentorship and research infrastructure at the University of Pennsylvania and The Children's Hospital of Philadelphia that have supported Dr. Abend?s current productivity. The plan involves (1) didactic coursework focused on clinical trials, patient outcomes research, regulatory issues, and team-science skills, and (2) training from investigators experienced with each component required to conduct clinical trials focused on seizure management in critically ill children, and (3) practical experience conducting a clinical trial. This training will allow Dr. Abend to develop and execute subsequent clinical trials of neuroprotective strategies in critically ill children. Summary: The research aims, training plan, and world-class clinical research infrastructure at the University of Pennsylvania and The Children's Hospital of Philadelphia assure that Dr. Abend will become an even more productive independent clinical investigator who will excel at leading multi-site clinical trials focused on improving outcomes for critically ill children with acute brain injuries.